tbuckley/cabot-search huggingface dataset:
Small volume blood-brain barrier opening in macaques with a 1 MHz ultrasound phased array
Authors: Thomas J. Manuel, Michelle K. Sigona, M. Anthony Phipps, Jiro Kusunose, Huiwen Luo, Pai-Feng Yang, Allen T. Newton, John C. Gore, William Grissom, Li Min Chen, Charles F. Caskey
Journal: Journal of Controlled Release (2023)
Health Insurance and Differences in Infant Mortality Rates in the US
Authors: Desalyn L. Johnson, Waldemar A. Carlo, A. K. M. Fazlur Rahman, Rachel Tindal, Sarah G. Trulove, Mykaela J. Watt, Colm P. Travers
Journal: JAMA Network Open (2023)

Importance Health insurance status is associated with differences in access to health care and health outcomes. Therefore, maternal health insurance type may be associated with differences in infant outcomes in the US. Objective To determine whether, among infants born in the US, maternal private insurance compared with public Medicaid insurance is associated with a lower infant mortality rate (IMR). Design, Setting, and Participants This cohort study used data from the Centers for Disease Control and Prevention (CDC) Wide-Ranging Online Data for Epidemiologic Research expanded linked birth and infant death records database from 2017 to 2020. Hospital-born infants from 20 to 42 weeks of gestational age were included if the mother had either private or Medicaid insurance. Infants with congenital anomalies, those without a recorded method of payment, and those without either private insurance or Medicaid were excluded. Data analysis was performed from June 2022 to August 2023. Exposures Private vs Medicaid insurance. Main Outcomes and Measures The primary outcome was the IMR. Negative-binomial regression adjusted for race, sex, multiple birth, any maternal pregnancy risk factors (as defined by the CDC), education level, and tobacco use was used to determine the difference in IMR between private and Medicaid insurance. The χ 2 or Fisher exact test was used to compare differences in categorical variables between groups. Results Of the 13 562 625 infants included (6 631 735 girls [48.9%]), 7 327 339 mothers (54.0%) had private insurance and 6 235 286 (46.0%) were insured by Medicaid. Infants born to mothers with private insurance had a lower IMR compared with infants born to those with Medicaid (2.75 vs 5.30 deaths per 1000 live births; adjusted relative risk [aRR], 0.81; 95% CI, 0.69-0.95; P = .009). Those with private insurance had a significantly lower risk of postneonatal mortality (0.81 vs 2.41 deaths per 1000 births; aRR, 0.57; 95% CI, 0.47-0.68; P &amp;amp;lt; .001), low birth weight (aRR, 0.90; 95% CI, 0.85-0.94; P &amp;amp;lt; .001), vaginal breech delivery (aRR, 0.80; 95% CI, 0.67-0.96; P = .02), and preterm birth (aRR, 0.92; 95% CI, 0.88-0.97; P = .002) and a higher probability of first trimester prenatal care (aRR, 1.24; 95% CI, 1.21-1.27; P &amp;amp;lt; .001) compared with those with Medicaid. Conclusions and Relevance In this cohort study, maternal Medicaid insurance was associated with increased risk of infant mortality at the population level in the US. Novel strategies are needed to improve access to care, quality of care, and outcomes among women and infants enrolled in Medicaid.
The CD4+ T cell repertoire specific for citrullinated peptides shows evidence of immune tolerance
Authors: Matthew K. McElwee, Thamotharampillai Dileepan, Shawn A. Mahmud, Marc K. Jenkins
Journal: The Journal of Experimental Medicine (2023)

Rheumatoid arthritis occurs most often in people who express HLA-DR molecules containing a five aa "shared epitope" in the β chain. These MHCII molecules preferentially bind citrullinated peptides formed by posttranslational modification of arginine. Citrullinated peptide:HLA-DR complexes may act as arthritis-initiating neo-antigens for CD4+ T cells. Here, we used fluorophore-conjugated HLA-DR tetramers containing citrullinated peptides from human cartilage intermediate layer protein, fibrinogen, vimentin, or enolase 1 to track cognate CD4+ T cells. Immunization of HLA-DR transgenic mice with citrullinated peptides from vimentin or enolase 1 failed to cause any expansion of tetramer-binding cells, whereas immunization with citrullinated peptides from cartilage intermediate layer protein or fibrinogen elicited some expansion. The expanded tetramer-binding populations, however, had lower T helper 1 and higher regulatory T cell frequencies than populations elicited by viral peptides. These results indicate that HLA-DR-bound citrullinated peptides are not neo-antigens and induce varying degrees of immune tolerance that could pose a barrier to rheumatoid arthritis.
Implementation of a broad public health approach to COVID-19 in Sweden, January 2020 to May 2022
Authors: Anders Tegnell, Anna Bessö, Britta Björkholm, Sara Byfors, Johan Carlson, Karin Tegmark Wisell
Journal: Eurosurveillance (2023)

In 2020, the world had to adapt to a pandemic caused by a then novel coronavirus. In addition to its direct impact on morbidity and mortality, the COVID-19 pandemic brought unprecedented control measures and challenges to both individuals and society. Sweden has been seen by many as an outlier in the management of the pandemic. It is therefore of special interest to document the actual management of the pandemic in Sweden during its first 2 years and how public health was affected. In the authors opinion, within the Swedish context, it has been possible to achieve a similar level of effect on mortality and morbidity through recommendations as was achieved through stringent legal measures in comparable countries. This is supported by comparisons of excess mortality that have been published. Furthermore, we see in the available data that the consequences on mental health and living habits were very limited for the majority of the population. Trust in public institutions is high in Sweden, which has been important and is part of the context that made it possible to manage a pandemic with relatively ‘soft’ measures. We acknowledge challenges in protecting certain vulnerable groups, particularly during the first and second wave.
Recent updates on pharmacologic therapy in non-alcoholic fatty liver disease
Authors: Young Chang, Soung Won Jeong, Jae Young Jang
Journal: Clinical and Molecular Hepatology (2023)

Since there are currently no US Food and Drug Administration (FDA)-approved drugs for the treatment of non-alcoholic steatohepatitis (NASH), various NASH treatments are under development for a wide range of targets.Several promising agents have recently failed in phase 3 trials, including selosertib, 1 elafibranor, and cenicriviroc, 2 and now five pharmacologic agents-obeticholic acid (OCA), resmetirom, aramchol, lanifibranor, and semaglutide-are being evaluated in large, histology-based phase 3 trials (Table 1).OCA, a farnesoid X receptor agonist, has been demonstrated to reduce hepatic fibrosis without worsening NASH in the 18-month interim analysis of the REGENERATE phase 3 trial, 3 and its anti-fibrotic effect and long-term favorable safety profile have recently been validated. 4wever, in May 2023, the FDA rejected the new drug application of OCA for pre-cirrhotic NASH, concerning safety issues such as hepatotoxicity, cholelithiasis, and pruritus, while its efficacy is modest.Resmetirom is a liver-targeted, thyroid hormone receptor ß (THR-ß)selective agonist.Based on the promising results in the phase 2 clinical trial, 5 phase 3 trials evaluating the efficacy of resmetirom in patients with NASH presenting with compensated cirrhosis (MAESTRO-NASH-Outcomes trial) and stage 2-3 fibrosis (MAESTRO-NASH) are ongoing.In the interim analysis of MAESTRO-NASH trial, which included 955 patients, histological NASH resolution and fibrosis reduction end points were achieved after 52 weeks of treatment. 6Until now resmetirom is the only drug showing both NASH and fibrosis improvement in a phase 3 trial.The antidiabetic drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP), are attractive candidates for the treatment of NASH, considering their beneficial metabolic effects.These are incretins that stimulate insulin secretion from pancreatic β cells in response to food ingestion.Semaglutide, a GLP-1 RA, showed a significant dose-dependent NASH resolution without worsening of fibrosis in a phase 2 randomized controlled trial (RCT) involving patients with NASH and stage 1-3 fibrosis. 7A phase 3 trial of semaglutide for NASH-related fibrosis
Disparities in outcomes and access to therapy options in hepatocellular carcinoma
Authors: Sara Beltrán Ponce, Yevgeniya Gokun, Francisca Douglass, Laura Dawson, Eric Miller, Charles R Thomas, Kenneth Pitter, Lanla Conteh, Dayssy A Diaz
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Hepatocellular carcinoma (HCC) disproportionately impacts racial and ethnic minorities and patients with lower socioeconomic status. These social determinants of health (SDH) lead to disparities in access to care and outcomes. We aim to understand the relationship between SDH and survival and locoregional treatment options in HCC. Methods Using the National Cancer Database, we evaluated survival and access locoregional treatments including non-transplant surgery, liver transplant (LT), and liver-directed radiation therapy (LDRT) in patients with HCC diagnosed between 2004 and 2017. Variables including clinical stage, age, sex, race, income, rurality, year of diagnosis, facility type (FT), Charlson-Deyo score (CD), and insurance were evaluated. Cox proportional hazards multivariable regression and dominance analyses were used for analyses. Results In total, 140 340 patients were included. Worse survival was seen with advanced stage, older age, Black race, rurality, public insurance, treatment at a nonacademic center, and lower income. The top predictors for survival included stage, age, and income. Completion of non-transplant surgery was best predicted by stage, FT, and insurance type, whereas LT was predicted by age, year of diagnosis, and CD score. LDRT utilization was most associated with year of diagnosis, FT, and CD score. Conclusion For patients with HCC, survival was predicted primarily by stage, age, and income. The primary sociodemographic factors associated with access to surgical treatments, in addition to FT, were insurance and income, highlighting the financial burdens of health care. Work is needed to address disparities in access to care, including improved insurance access, addressing financial inequities and financial toxicities of treatments, and equalizing care opportunities in community centers.
Why are squamous cancers so aggressive in recessive dystrophic epidermolysis bullosa? Can we find new therapeutic approaches?
Authors: Ryan F L O’Shaughnessy
Journal: British Journal of Dermatology (2023)

Journal Article Corrected proof Why are squamous cancers so aggressive in recessive dystrophic epidermolysis bullosa? Can we find new therapeutic approaches? Get access Ryan F L O’Shaughnessy Ryan F L O’Shaughnessy Writing - original draft Centre for Cell Biology and Cutaneous Research, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, UK Email: r.f.l.oshaughnessy@qmul.ac.uk Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljad392, https://doi.org/10.1093/bjd/ljad392 Published: 13 October 2023 Article history Received: 03 October 2023 Accepted: 06 October 2023 Published: 13 October 2023 Corrected and typeset: 03 November 2023
Multifaceted functions of Drp1 in hypoxia/ischemia-induced mitochondrial quality imbalance: from regulatory mechanism to targeted therapeutic strategy
Authors: Shuai Hao, He Huang, Rui-Yan Ma, Xue Zeng, Chen-Yang Duan
Journal: Military Medical Research (2023)

Abstract Hypoxic-ischemic injury is a common pathological dysfunction in clinical settings. Mitochondria are sensitive organelles that are readily damaged following ischemia and hypoxia. Dynamin-related protein 1 (Drp1) regulates mitochondrial quality and cellular functions via its oligomeric changes and multiple modifications, which plays a role in mediating the induction of multiple organ damage during hypoxic-ischemic injury. However, there is active controversy and gaps in knowledge regarding the modification, protein interaction, and functions of Drp1, which both hinder and promote development of Drp1 as a novel therapeutic target. Here, we summarize recent findings on the oligomeric changes, modification types, and protein interactions of Drp1 in various hypoxic-ischemic diseases, as well as the Drp1-mediated regulation of mitochondrial quality and cell functions following ischemia and hypoxia. Additionally, potential clinical translation prospects for targeting Drp1 are discussed. This review provides new ideas and targets for proactive interventions on multiple organ damage induced by various hypoxic-ischemic diseases.
Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Authors: Chenxi Ma, Chengzhe Yang, Ai Peng, Tianyong Sun, Xiaoli Ji, Jun Mi, Li Wei, Song Shen, Qiang Feng
Journal: Molecular Cancer (2023)

Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population that plays a crucial role in remodeling the tumor microenvironment (TME). Here, through the integrated analysis of spatial and single-cell transcriptomics data across six common cancer types, we identified four distinct functional subgroups of CAFs and described their spatial distribution characteristics. Additionally, the analysis of single-cell RNA sequencing (scRNA-seq) data from three additional common cancer types and two newly generated scRNA-seq datasets of rare cancer types, namely epithelial-myoepithelial carcinoma (EMC) and mucoepidermoid carcinoma (MEC), expanded our understanding of CAF heterogeneity. Cell-cell interaction analysis conducted within the spatial context highlighted the pivotal roles of matrix CAFs (mCAFs) in tumor angiogenesis and inflammatory CAFs (iCAFs) in shaping the immunosuppressive microenvironment. In patients with breast cancer (BRCA) undergoing anti-PD-1 immunotherapy, iCAFs demonstrated heightened capacity in facilitating cancer cell proliferation, promoting epithelial-mesenchymal transition (EMT), and contributing to the establishment of an immunosuppressive microenvironment. Furthermore, a scoring system based on iCAFs showed a significant correlation with immune therapy response in melanoma patients. Lastly, we provided a web interface ( https://chenxisd.shinyapps.io/pancaf/ ) for the research community to investigate CAFs in the context of pan-cancer.
Bendamustine vs. fludarabine/cyclophosphamide lymphodepletion prior to BCMA CAR-T cell therapy in multiple myeloma
Authors: Surbhi Sidana, Hitomi Hosoya, Alexandria Jensen, Lawrence Liu, Anmol Goyal, Vanna Hovanky, Bita Sahaf, Sushma Bharadwaj, Theresa Latchford, Sally Arai, Sheryl Leahy, Matthew Mei, Lihua E. Budde, Lori S. Muffly, Matthew J. Frank, Saurabh Dahiya, Myo Htut, David Miklos, Murali Janakiram
Journal: Blood Cancer Journal (2023)

Bendamustine vs. fludarabine
Genome Instability and DNA Repair in Somatic and Reproductive Aging
Authors: Stephanie Panier, Siyao Wang, Björn Schumacher
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

Genetic material is constantly subjected to genotoxic insults and is critically dependent on DNA repair. Genome maintenance mechanisms differ in somatic and germ cells as the soma only requires maintenance during an individual's lifespan, while the germline indefinitely perpetuates its genetic information. DNA lesions are recognized and repaired by mechanistically highly diverse repair machineries. The DNA damage response impinges on a vast array of homeostatic processes and can ultimately result in cell fate changes such as apoptosis or cellular senescence. DNA damage causally contributes to the aging process and aging-associated diseases, most prominently cancer. By causing mutations, DNA damage in germ cells can lead to genetic diseases and impact the evolutionary trajectory of a species. The mechanisms ensuring tight control of germline DNA repair could be highly instructive in defining strategies for improved somatic DNA repair. They may provide future interventions to maintain health and prevent disease during aging.
Within-Host Evolution of Bacterial Pathogens in Acute and Chronic Infection
Authors: John P. Dekker
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

Bacterial pathogens undergo remarkable adaptive change in response to the selective forces they encounter during host colonization and infection. Studies performed over the past few decades have demonstrated that many general evolutionary processes can be discerned during the course of host adaptation, including genetic diversification of lineages, clonal succession events, convergent evolution, and balanced fitness trade-offs. In some cases, elevated mutation rates resulting from mismatch repair or proofreading deficiencies accelerate evolution, and active mobile genetic elements or phages may facilitate genome plasticity. The host immune response provides another critical component of the fitness landscapes guiding adaptation, and selection operating on pathogens at this level may lead to immune evasion and the establishment of chronic infection. This review summarizes recent advances in this field, with a special focus on different forms of bacterial genome plasticity in the context of infection, and considers clinical consequences of adaptive changes for the host.
Role of the Microenvironment in Glioma Pathogenesis
Authors: Maya Anjali Jayaram, Joanna J. Phillips
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

Gliomas are a diverse group of primary central nervous system tumors that affect both children and adults. Recent studies have revealed a dynamic cross talk that occurs between glioma cells and components of their microenvironment, including neurons, astrocytes, immune cells, and the extracellular matrix. This cross talk regulates fundamental aspects of glioma development and growth. In this review, we discuss recent discoveries about the impact of these interactions on gliomas and highlight how tumor cells actively remodel their microenvironment to promote disease. These studies provide a better understanding of the interactions in the microenvironment that are important in gliomas, offer insight into the cross talk that occurs, and identify potential therapeutic vulnerabilities that can be utilized to improve clinical outcomes.
Clonal Hematopoiesis, Inflammation, and Hematologic Malignancy
Authors: Rashmi Kanagal-Shamanna, David B. Beck, Katherine R. Calvo
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond.
Comparative Pathogenesis of Severe Acute Respiratory Syndrome Coronaviruses
Authors: Jingshu Zhang, Melanie Rissmann, Thijs Kuiken, Bart L. Haagmans
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

Over the last two decades the world has witnessed the global spread of two genetically related highly pathogenic coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. However, the impact of these outbreaks differed significantly with respect to the hospitalizations and fatalities seen worldwide. While many studies have been performed recently on SARS-CoV-2, a comparative pathogenesis analysis with SARS-CoV may further provide critical insights into the mechanisms of disease that drive coronavirus-induced respiratory disease. In this review, we comprehensively describe clinical and experimental observations related to transmission and pathogenesis of SARS-CoV-2 in comparison with SARS-CoV, focusing on human, animal, and in vitro studies. By deciphering the similarities and disparities of SARS-CoV and SARS-CoV-2, in terms of transmission and pathogenesis mechanisms, we offer insights into the divergent characteristics of these two viruses. This information may also be relevant to assessing potential novel introductions of genetically related highly pathogenic coronaviruses.
Cancer as a Disease of Development Gone Awry
Authors: Ben Z. Stanger, Geoffrey M. Wahl
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

In the 160 years since Rudolf Virchow first postulated that neoplasia arises by the same law that regulates embryonic development, scientists have come to recognize the striking overlap between the molecular and cellular programs used by cancers and embryos. Advances in cancer biology and molecular techniques have further highlighted the similarities between carcinogenesis and embryogenesis, where cellular growth, differentiation, motility, and intercellular cross talk are mediated by common drivers and regulatory networks. This review highlights the many connections linking cancer biology and developmental biology to provide a deeper understanding of how a tissue's developmental history may both enable and constrain cancer cell evolution.
Epigenomic Characterization of Lymphoid Neoplasms
Authors: Martí Duran-Ferrer, José Ignacio Martín-Subero
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

Lymphoid neoplasms represent a heterogeneous group of disease entities and subtypes with markedly different molecular and clinical features. Beyond genetic alterations, lymphoid tumors also show widespread epigenomic changes. These severely affect the levels and distribution of DNA methylation, histone modifications, chromatin accessibility, and three-dimensional genome interactions. DNA methylation stands out as a tracer of cell identity and memory, as B cell neoplasms show epigenetic imprints of their cellular origin and proliferative history, which can be quantified by an epigenetic mitotic clock. Chromatin-associated marks are informative to uncover altered regulatory regions and transcription factor networks contributing to the development of distinct lymphoid tumors. Tumor-intrinsic epigenetic and genetic aberrations cooperate and interact with microenvironmental cells to shape the transcriptome at different phases of lymphoma evolution, and intraclonal heterogeneity can now be characterized by single-cell profiling. Finally, epigenetics offers multiple clinical applications, including powerful diagnostic and prognostic biomarkers as well as therapeutic targets.